The applicant seeks a research project grant (RO1) to study the induction of immunoglobulin gene rearrangements in surface IgM+ B lymphocytes. Preliminary data is presented suggesting that encounter with autoantigen can induce the rearrangement of fight chain genes in immature sIgM+ B-cells of the bone marrow. This was observed in transgenic mice bearing rearranged, functional Ig genes encoding an antibody specific for MHC class I alloantigens, in which the effect of different forms of autoantigen on B-cell development could be assessed. This proposed mechanism for B-cell tolerance in immature B-cells is termed the Receptor Editing hypothesis. The Specific Aim of this proposal is to test the Receptor Editing hypothesis. This hypothesis proposes that in autoreactive, immature B lymphocytes sIgM crosslinking by self antigens induces secondary immunoglobulin gene rearrangements that can alter their receptors and render them non-autoreactive. The long-term goal of these studies is to understand how the specificities of the pre-immune lymphocyte repertoire are shaped by the internal environment and to identify possible defects in these processes in situations of immune dysfunction.